FDA issues final guidance on rare disease drug development

The US Food and Drug Administration (FDA) finalized guidance on drug development programs for rare diseases, eliminating a section on natural history and providing additional considerations related to patient and caregiver input and pediatric populations.

The final guidance, issued on 26 December 2023, is aimed at assisting orphan drug sponsors and covers nonclinical pharmacology and toxicology, trial design and endpoint selection, the evidence standard for establishing safety and effectiveness, and drug manufacturing issues.

“FDA recognizes that rare diseases are highly diverse with varying prevalence, rates of progression, and degrees of heterogeneity that can affect both clinical manifestations and disease courses even within a condition. Further complexity is added depending on what is known about a disease’s natural history and pathophysiology. As such, no one program can be designed exactly like another,” agency officials wrote in the final guidance.

The document replaces draft guidance, which was issued in early 2019. In a Federal Register notice announcing the final guidance, FDA said it made several changes to the final version based on public comments. (RELATED: Patient Groups, Industry Seek Changes to Rare Disease Drug Guidance, Regulatory Focus 04 April 2019; FDA Revises Draft Guidance on Rare Diseases, Regulatory Focus 16 January 2019)

For instance, the final guidance removes a section on natural history, which is covered in a separate draft guidance document issued in March 2019. The final guidance document also adds information on the use of external controls, a dedicated section on safety issues, considerations for changes to the drug substance or manufacturing process, and sections that address input from patients and advocacy groups in drug development and considerations for pediatric participants.

SDLTs and nonclinical flexibilities

In the guidance, FDA signaled its intention to apply the “broadest flexibility” for products being developed for the treatment of severely debilitating or life-threatening rare diseases (SDLTs).

“For products being developed for SDLT rare disease indications, clinical investigations can often proceed with modifications to the typical nonclinical development programs described in guidance. The degree of flexibility afforded to such programs may depend on a variety of factors, such as the adequacy of current treatment options, the mechanism of the drug, the safety findings from the available data, and the expected rate of progression to mortality or irreversible morbidity,” FDA wrote.

Orphan drug sponsors for SDLT rare disease indications are generally expected to provide data on primary and secondary pharmacology; safety pharmacology; in vitro absorption, distribution, metabolism and excretion; and genetic toxicity at the time of submission of an investigational new drug application (IND). However, adjustments in the nonclinical submissions for SDLT rare disease indications may be appropriate for the repeat-dose general toxicology study duration and timing of submission, species selection, developmental and reproductive toxicity assessment, and the carcinogenicity assessment, according to the guidance.

“The suitability of any or all of the above flexibilities to any given development program needs to be determined on a case-by-case basis. Therefore, FDA strongly encourages the sponsor to discuss the proposed approach with the review division to obtain concurrence with the sponsor’s proposed nonclinical development program,” the agency wrote.

External controls and prevalence estimates

The final guidance also acknowledges the interest in using external controls in clinical investigations for serious rare disease with unmet medical need, allowing a comparison between study participants and an external group that did not receive the same treatment. Due to the limitations of external controls, such as lack of blinding, this type of design is typically reserved for studies where the drug effect is “large and self evident” or can be demonstrated in diseases with a well understood natural history, according to FDA.

“The suitability of an externally controlled clinical investigation design warrants a case-by-case assessment, and early discussion with the relevant review division is recommended,” FDA wrote in the final guidance.

The agency also outlines expectations about accurately estimating disease prevalence to help determine adequate study enrollment. The guidance notes that prevalence estimates should include all phenotypic subtypes of a disease that are anticipated to respond to the investigational drugs, such as infantile, juvenile and adult. Additionally, orphan drug sponsors should calculate prevalence estimates for any countries where study sites are being considered and provide individual sources of published prevalence estimates instead of averages.

Patient input and pediatric considerations

The final guidance also encourages orphan drug sponsors to involve patients, caregivers and advocates in the drug development process.

“Patient input can provide important information about patients’ experiences, perspectives, needs, and priorities that can be incorporated throughout the drug development process. This engagement can take many forms, such as providing solicited consultation on scientific issues (e.g., clinically meaningful treatment effects), working with industry sponsors as they design and conduct clinical investigations, and contributing to patient-focused drug development initiatives,” the agency wrote.

FDA also “strongly encourages” sponsors to study the drug in all pediatric populations that are relevant, from birth to age 17, and to develop pediatric formulations of drugs to allow for accurate dosing for the youngest patients. In cases where clinical studies include both pediatric and adult participants, FDA advised sponsors to consider the relevance of endpoints to both groups and assess whether results could be combined in a single statistical analysis.

“Careful planning for a drug being developed to treat a rare disease in children is important to maximize the efficiency and increase the likelihood of success of the drug’s clinical development program,” FDA wrote in the final guidance. “Such planning should include discussions with FDA early in drug development about the epidemiology of the rare disease and plans for inclusion of pediatric participants in clinical studies.”

Federal Register notice

Final Guidance

FDA issues final guidance on rare disease drug development

Related topics

Recommended content

Welcome to the new RAPS Digital Experience